Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• This invention relates to pharmaceutical compositions confining certain diarylimidazole derivatives which selectively bind to human NPY receptors. Some of such diarylimidazoles are believed to be novel.
• the invention further relates to the use of such compounds in treating feeding disorders such as obesity and bulimia as well as certain cardiovascular diseases such as essential hypertension.
• Neuropeptides known as Neuropeptide Y are believed to have a role in a variety of functions in the body and in particular have been associated with stimulation of appetite but also to effect anxiolysis and regulation of coronary tone. Such compounds bind to a number of different receptor sites.
• U.S. Patent 5,571,695 (Selbie et al.) describes the genomic DNA sequences that code for the Y-l receptor.
• U.S. Patent 5,554,621 (Poindexter et al.) describes certain 4-phenyl dihydropyridines that are NPY antagonists and noted the existence of at least five receptor subtypes for NPY.
• Patent 5,545,549 (Gerald et al) describes the human Y2 receptor and the DNA coding for it.
• U.S. Patent 5,516,653 (Bard et al.) describes the human Y4 receptor and the DNA coding for it.
• U.S. Patent 5,602,024 (Gerald et al) describes the human Y5 receptor and the DNA coding for it. It states that this receptor seems to be the most significant for appetite stimulation.
• diarylimidazoles are known for a variety of uses.
• European Patent Publication 627499 (Shikoku Chemicals Corporation) and its United States equivalent
• U. S. Patent 5,498,301 (Hirao) describe the use of 2,4- diphenylimidazole and 2,4-di ⁇ henyl-5-methyl imidazoles as water based surface treating agents for use on copper surfaces and compares their activity to that of 2,4,5- triphenylimidazole.
• the 2- ⁇ henyl group may be substituted by alkyl or halo groups and the 4- ⁇ henyl group by alkyl, halo, alkoxy, di-loweralkylamino, cyano or nitro groups.
• PCT Publication WO 95/04274 (Nippon Soda Co. Ltd.) describes the use of a wide range of imidazoles for pest control including 2-(optionally halogenated)phenyl-4-(optionally halogenated) phenylimidazoles.
• East German patent publication 299059 (Chemical Abstracts 117:131199) describes 2-(2-hydroxyphenyl)-4-substituted imidazoles wherein the substituent in the 4 position may be an optionally substituted phenyl group and the 5 position may be substituted by a phenyl or alkyl group.
• East German patent publication 297816 (Chemical Abstracts 116:214504) describes 2-arylimidazole compounds wherein the 4 or 5 positions may have aryl substituents of use as lipoxygenase inhibitors.
• German Patent Publication 3917677 (Chemical Abstracts 115:25542) describes 2-(4-hydroxy-3,5-di-tert.-butyl)phenyl-4-(4-dialkylamino)phenylimidazoles of use as chromogenic substrates in analytical redox reactions.
• the 4-phenyl group and the 5 position of the imidazole ring may be further substituted by alkyl groups.
• German Patent Publication 3411997 (Chemical Abstracts 104:145136) describes compounds of use as redox indicators including 2-(substituted phenyl)-4- (substituted phenyl) imidazoles.
• European Patent Publication 0131973 (Instituto de Angeli S. p. A.) describes the use of certain aryl imidazoles, including 2-phenyl-4-(4-nitro-phenyl)-lH- imidazole and 2-phenyl-4-(4-amino-phenyl)-lH-imidazole as intermediates in the production of amidines useful as H 2 receptor blocking agents.
• C. A Registry Nos 135466-37-4, 135466-36-3; 135437-73-9; 135437-72-8; 135437-71-7; 135437-68-2; 135437-66-0; 135437-65-9; 135437-64-8; 135437-63-7; 135437-62-6; 135437-61-5; 135437-60-4 and 135437-59-1); analogous 2(lH)-3,4-dihydroquinolones (C.A.
• This invention provides pharmaceutical compositions comprising compounds of Formula I which interact with Neuropeptide Y receptors and in particular with NP Y5 receptors and methods of treatment of conditions susceptible to such interactions. It further relates to the use of such compounds in treating feeding disorders such as obesity and bulima as well as certain cardiovascular diseases such as essential hypertension. Suitable compounds are those of Formula I:
• Rj is an unsubstituted or mono, di or trisubstituted aryl group wherein said aryl group is mono or bicyclic, in which case only the ring bound to the imidazole group ring need be aromatic, and said aryl group may be carbocyclic or contain up to 2 hetero atoms which may be nitrogen, oxygen or sulfur, and said substituents are selected from the group consisting of halogen, trihalomethyl, cyano, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms (which alkyl or alkoxy groups themselves may be substituted by an amino or mono- or di- alkyl amino group or an acyl group), straight or branched chain lower thioalkoxy having 1-6 carbon atoms, acyloxy groups, a ino, amino mono or disubstituted with straight or branched chain lower alkyl having 1-6 carbon atoms, said alkyl
• R 2 and R 3 is selected from the group consisting of hydrogen, hydroxymethyl, alkoxymethyl having up to 6 carbon atoms in each alkoxy group, straight or branched chain lower alkyl having 1-6 carbon atoms, cyano, or a carboxylic or carboxylate ester group wherein the esterifying group typically contains up to six carbon atoms.
• R 2 and R 3 is an aryl group which is either unsubstituted or mono, di or trisubstituted wherein said aryl groups are mono or bicyclic (in which case only the ring bound to the imidazole grouping need be aromatic) and may be carbocyclic or contain up to 2 hetero atoms and said substituents are selected from the group consisting of halogen, trihalomethyl, cyano, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms (which alkyl or alkoxy groups themselves may be substituted by amino or a mono- or di- alkyl amino groupor an acyl group), straight or branched chain lower thioalkoxy having 1-6 carbon atoms, acyloxy groups, amino, amino mono or disubstituted with straight or branched chain lower alkyl having 1-6 carbon atoms (said alkyl groups being optionally substituted with
• NP Y5 receptors are useful in the diagnosis and treatment in mammals of feeding disorders such as obesity and bulimia as well as certain cardiovascular diseases such as essential hypertension and congestive heart failure.
• R is an aryl group, which may be unsubstituted or mono, di or trisubstituted.
• the aryl groups from which R, may be selected are typically mono or bicyclic groups, in which case only the ring bound to the imidazole group need be aromatic, and may be carbocyclic or heterocyclic containing up to 4 hetero atoms but no more than 2 hetero atoms in each ring.
• each ring of the aryl group is a five or six membered ring.
• Suitable aryl groups include phenyl, naphthyl, indanyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl, benzofuranyl, thianaphthyl, isoindolyl, isobenzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, quinoxalinyl, cinnolinyl 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydroindolyl, phenomorpholinyl, benzodioxazinyl, phenothiomorpholinyl and methylenedioxyphenyl groups.
• Suitable substituents include: halogen, trihalomethyl, cyano, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, which alkyl and alkoxy groups themselves may be substituted by an amino or a mono- or di-alkylamino group or a mono- or di-alkaryl group such as benzyl or by an acyl group, straight or branched chain lower thioalkoxy having 1-6 carbon atoms, acyloxy groups such as alkanoyloxy groups of from 2 to 7 carbon atoms, such as acetoxy, and aroyloxy groups such as benzoyloxy, amino, amino mono or disubstituted with straight or branched chain lower alkyl having 1-6 carbon atoms, said alkyl groups being optionally substituted with a hydroxy or amino group, mono or disubstituted carbamyl groups wherein the substituent is lower alky
• any two adjacent substituents may be represented as -X-(CH 2 ) n -Y-(CH 2 ) m -Z- where X, Y and Z are either a direct bond, oxygen, sulfur, or NR where R is hydrogen of lower alkyl and n and m are 1,2 or 3.
• R 2 and R 3 is selected from hydrogen, hydroxymethyl, alkoxy- methyl having from 1 to 6 carbon atoms in the alkyl group, straight or branched chain lower alkyl having 1-6 carbon atoms, cyano, or a carboxylic or carboxylate ester group wherein the esterifying group typically has up to six carbon atoms.
• the other of R 2 and R 3 is an aryl group either unsubstituted or mono, di or trisubstituted. Suitable aryl groups are mono or bicyclic and may be carbocyclic or contain up to 2 hetero atoms.
• Suitable substituents include: halogen, trihalomethyl, cyano, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, (which alkyl or alkoxy groups may be substituted with an amino or a mono- or dialkyl amino group or a mono- or di-alkaryl amino group or an acyl group), straight or branched chain lower thioalkoxy having 1 -6 carbon atoms, acyl groups such as acetyl, acyloxy groups such as alkanoyloxy groups of from 2 to 7 carbon atoms, such as acetoxy, and aroyloxy groups such as benzoyloxy, amino, amino mono or disubstituted with straight or branched chain lower alkyl having 1-6 carbon atoms, said all groups being optionally substituted with a hydroxy or amino group, mono or di substituted carbamyl groups wherein the CO group is bound to the
• any two adjacent substituents may be represented as -X-(CH 2 ) n -Y-(CH 2 ) m -Z- where X Y and Z are either a direct bond, oxygen, sulfur, or NR where R is hydrogen of lower alkyl and n and m are 1, 2 or 3.
• alkyl includes branched and straight chain alkyl groups and cycloalkyl groups. Such alkyl groups may be interrupted by an oxygen or sulfur atom.
• Alkyl further comprises groups containing both a cyclic and an acyclic portion.
• alkyl groups referred to in this application have from 1 to 8 carbon atoms and any cyclo alkyl group or portion of an alkyl group will have from three to six carbon atoms in the ring and may optionally contain some unsaturation.
• a "lower alkyl” group is an alkyl group as just defined containing up to six carbon atoms.
• “Acyl” groups may contain alkyl, aryl or aralkyl groups but normally no more than 8 carbon atoms.
• alkaryl is used to denote groups such as benzyl and phenylethyl groups. It will be recognized by those skilled in the art that several of the compounds of use in the present invention may exist in tautomeric form. In such cases, reference to a particular compound encompasses both tautomeric forms.
• aryl group of R is selected from aryl monocyclic groups which may be carbocyclic or contain up to two hetero atoms (N, O, or S) and is either ⁇ nsubstituted or is substituted by up to three groups such as halogen, trihalomethyl, cyano, hydroxy, straight or branched chain lower alkyl of 1- 6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, straight or branched chain lower thioalkoxy having 1-6 carbon atoms, acyloxy groups, amino, amino mono or disubstituted with straight or branched chain lower alkyl having 1-6 carbon atoms, said alkyl groups being optionally substituted with a hydroxy or amino group, mono or di-alkyl carbamates having up to 6 carbon atoms in each alkyl group or mono or diaryl carbamates.
• any 2 adjacent substituents on an aryl ring may be represented as -X(CH 2 ) ⁇ -Y-(CH 2 ) m -Z- where X Y and Z are either a direct bond, oxygen, sulfur, or NR where R is hydrogen or lower alkyl and n and m are 1, 2 or 3.
• R can most usefully be a phenyl, 4-fluorophenyl, pyridin-2-yl or a thiophene group.
• particularly useful non-aryl R 2 and R 3 groups include hydrogen, alkyl (as defined above).
• Particularly useful aryl groups for R 2 or R 3 include as phenyl, thienyl, pyridyl, and napthyl for example bearing up to three substituents selected from halo (especially chloro or fluoro), alkoxy (such as mefhoxy) and alkyl (such as methyl, ethyl groups.
• Particularly preferred groups include 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-bromophenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 3- cyanophenyl, 4-cyanophenyl, 4-methoxy-2-fluorophenyl, 4-ethoxy-2-fluorophenyl, 3- fluoro-4-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 3-acetylphenyl, naphthyl, l,4-benzodioxan-6-yl and benzo [b] morpholinyl, 4-alkyl (e.g.
• Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfmic, formic, toluene sulfonic, hydroiodic, acetic , mesylate and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
• R, and whichever of R 2 and R 3 is aryl are both phenyl, a bromophenyl group, a chlorophenyl group, 2,4-dichlorophenyl, a cyanophenyl group, 2-methoxyphenyl, 3-aminophenyl, 4-aminophenyl, 4-trifluoromethylphenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 3-acetylaminophenyl, 4-phenoxyphenyl or biphenyl;
• R is phenyl, whichever of R 2 and R 3 is aryl is 2- acetylaminophenyl, chlorophenyl, biphenyl, 4-aminophenyl, p-tolyl, xylyl, 4- methoxyphenyl, 4-dimethylaminophenyl, 4-bromophenyl or 4-hydroxy-2,5-di-tert.- butylphenyl, 3) when one of R 2 or R 3 is phenyl, R, is 2-hydroxyphenyl, 4- hydroxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 4-chlorophenyl, biphenyl, 2,4- dichlorophenyl, 2,4-xylyl, 4-cyanophenyl or 6-quinolyl; and 4) R, is 2-hydroxyphenyl when R 2 or R 3 is p-tolyl, R, is 4-hydroxy-3- methoxyphenyl when R 2 or R 3 is 4-dimethylaminoph
• diarylimidazoles of the above formula wherein R is 4-fluorophenyl, those wherein R 2 or R 3 is an N- substituted aminomethylphenyl group or is selected from the group consisting of naphthyl, cyanophenyl, N-substituted benzo[b]morpholine, 2H,3H-benzo[e]l,4-dioxin and N-substituted 2H,3H, 4H-benzo[e]l,4-thiazine.
• Compounds according to the invention include: 2(4-fluorophenyl)-4-(4- methoxyphenyl)imidazole hydrochloride, 2-(thienyl-2-yl)-4-(4-chlorophenyl)imidazole, 2-(4-fluorophenyl)-4-(4-chlorophenyl)imidazole hydrochloride, 2-phenyl-4-(3- fluoro-4-methoxyphenyl)imidazole hydrochloride.
• SK-M-MC cells were purchased from ATCC (Rockville, MD). Cells were maintained at 37°C and 5% CO 2 in Dulbecco's modified essential media (DMEM) with L glutamine and 110 mg/L sodium pyruvate, which was supplemented with 10% fetal bovine serum and 25 mM HEPES (pH 7.3). The binding assay was performed in 24-well plates (Falcon) when the cells were confluent.
• DMEM Dulbecco's modified essential media
• HEPES 25 mM HEPES
• DPBS Dulbecco's phosphate buffered saline
• binding buffer consisting of serum-free DMEM containing 0.5% bovine serum albumin, 0.1% bacitracin and 0.1 mM phenylmethylsulfonylfluoride was added to each well.
• the cells, the binding buffer, the drug dilution and [ 125 I]PYY were added to yield a final volume of 250 ⁇ l.
• Nonspecific binding was defined with 1 ⁇ M NPY (porcine or human, Bachem California).
• the plates were then put on ice and the wells were aspirated.
• the cells were washed twice with 0.5 ml of ice-cold DPBS. A dilute solution of Triton X-100 (1%) was then added to each well.
• Baculovirus-infected Sf9 cells expressing recombinant human NPY 5 receptors are harvested at 48 hours. At the time of harvest, cell pellets are resuspended in lysis buffer (20 mM Tris-HCl pH 7.4, 5 mM EDTA, 0.5 ⁇ g/ml leupeptin, 2 ⁇ g/ml Aprotonin and 200 HM PMSF) and homogenized using a Polytron (setting 3,25-30 seconds). Homogenates are centrifuged at 4 °C for 5 minutes at 200 x g ( ⁇ 1.5 rpm) to pellet the nuclei.
• the supernatant is collected into a fresh tube and centrifuged at 48,000 x g for 10 minutes. Pellets are washed once in lysis buffer and centrifuged. The final pellet is resuspended in PBS and stored in aliquots at -80 °C. Purified membranes are washed using PBS and resuspended in binding buffer (50 mM Tris(HCl), pH 7.4,5 mM KC1, 120 mM NaCl, 2 mM CaCl 2 , 1 mM MgCl 2 , 0.1% bovine serum albumin (BSA)).
• binding buffer 50 mM Tris(HCl), pH 7.4,5 mM KC1, 120 mM NaCl, 2 mM CaCl 2 , 1 mM MgCl 2 , 0.1% bovine serum albumin (BSA)
• Membranes (20 ⁇ g/reaction tube) are added to polypropylene tubes containing 0.050 nM [125Il]PYY(porcine), displacers ranging from 10-12 M to 10 12 M to 10 "5 M, and buffer to yield a final volume of 0.250 mL.
• Nonspecific binding is determined in the presence of 1 ⁇ M NPY(human) and accounts for 10% of total binding.
• the reaction is terminated by rapid vacuum filtration. Samples are filtered over presoaked GF/C Whatman filters (1.0% polyethylenemine) and rinsed 2 times with 5 mLs cold binding buffer without BSA.
• a gamma counter is used to count filters with a n efficiency of 85%.
• the compounds of general formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
• parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intra sternal injection or infusion techniques.
• a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier.
• One or more compounds of general formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
• compositions containing compounds of general formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
• compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
• Tablets contain the active ingredient in admixture with non -toxic pharmaceutically acceptable excipient which are suitable for the manufacture of tablets.
• excipient may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
• the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
• Formulations for oral use may also be presented as hard gelatin capsules 99/01128
• Aqueous suspensions contain the active materials in admixture with excipient suitable for the manufacture of aqueous suspensions.
• excipients are suspending agents, for example sodium carboxymethyl cellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyefhylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyefhylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
• dispersing or wetting agents may be a naturally-occurring phosphatide, for
• the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
• Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
• the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin, or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipient, for example sweetening, flavoring and coloring agents, may also be present.
• Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
• the oily phase may be a vegetable oil, for example olive oil or arachid oil, or a mineral oil, for example liquid paraffin or mixtures of these.
• Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose.
• Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
• the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
• the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides.
• fatty acids such as oleic acid find use in the preparation of injectables.
• the compounds of general formula I may also be administered in the form of suppositories for rectal administration of the drug.
• These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• Such materials are cocoa butter and polyethylene glycols.
• Compounds of general formula I may be administered parenterally in a sterile medium.
• the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
• adjuvants such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.
• Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above indicated conditions (about 0.5 mg to about 7 g per patient per day).
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient. Dosages to be used will depend upon the particular use to which the composition is to be used.
• the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
• R, R 2 and R are as defined above.
• the invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in them.
• Particularly preferred compounds include:
• Each cage is comprised of subassemblies of clear polymethylpentene (PMP), polycarbonate (PC), and stainless steel (SS). All parts disassemble for quick and accurate data collection and for cleaning.
• the entire cylinder-shaped plastic and stainless steel cages rests on a stainless steel stand and houses one animal.
• the animal is contained in the round Upper Chamber (PC) assembly (12cm high and 20cm in diameter) and rests on a stainless steel floor (20cm diameter).
• Two subassemblies are attached to the Upper Chamber.
• the first subassembly consists of a 5.5. feeding chamber (10cm long, 5 cm high and 5 cm wide) with a PC feeding draw attached to the bottom.
• the feeding drawer has two compartments: A food storage compartment with a capacity for approximately 50 grams of pulverized rat chow and a food spillage compartment.
• the food storage compartment is distal to the Upper Chamber while the spillage compartment is proximal to the Upper Chamber.
• the animal is allowed access to the pulverized chow by an opening in the 55 floor of the feeding chamber.
• the floor of the feeding chamber does not allow access to the food dropped into the spillage compartment.
• the second subassembly adjacent to the Upper Chamber includes a water bottle support, a P.C. water bottle (100ml capacity) and a graduated water spillage collection tube.
• the water bottle support funnels any spilled water into the water spillage collection tube.
• the lower chamber consists of a PMP Separating Cone, PMP collection funnel, PMP fluid (urine) collection tube (70ml capacity), and feces collection tube.
• the Separating Cone is attached to the top of the collection funnel which is attached to the bottom of the Upper Chamber.
• the urine runs off the Separating Cone onto the walls of the collection funnel and into the urine collection tub.
• the Separating Cone also separates the feces and funnels it into the feces Collection tube.
• a Ohaus portable Advanced Scale (I 0.1 g accuracy) is used to weigh the rats, food and water contains, and the urine and feces collection tubes. Procedure. The effects of the experimental compound on body weight, food and water consumption, and fecal and urinary excretion are assessed using the Metabolic Cages. Rats are weighed prior to the assignment to experimental groups. Assignment is made using a quasirandom method utilizing pre-assignment body weights to assure that the treatment groups had similar average body weight.
• mice All food is removed from the home cage the night before testing. On the test day, approximately 1 hour prior to dosing, the animals are weighed tot he nearest 0.5g. For oral drug administration the animals are dosed with either methyl cellulose (MC) or one does of experimental compound and returned to their home cage. For intravenous (IV) dosing, the animals are dosed with either PEG-400 or one dose of experimental compound. After the appropriate pretreat time each animal is placed into a Metabolic Cage for a 1 hour test session. Prior to testing, the feeding drawer filled water bottle, are weighed. In addition, the empty feces and urine collection tubes are weighed Following the test session, the rats are removed from the metabolic cages, weighted, and returned to their home cages. The food and water containers, as well as the feces and urine collection tubes, are then weighed and recorded.
• MC methyl cellulose
• IV intravenous
• the experimental compound is suspended in 0.5% methyl cellulose (MC).
• Experimental compound or MC is administered orally (PO) in a dosing volume of IOml/kg.
• Drug is made into a homogenous suspension by stirring and ultrasonication.
• the drug or vehicle suspension is administered 45-60 min prior to test via 6cm piece of polyethylene (PE 90) tubing attached via a Leur lock hub to a 5cc Becton Dickson syringe.
• IV intravenous
• PEG-400 50% distilled water solution.
• the animals are dosed with either PEG-400 (1 to 4 ml/kg) or one dose of experimental compound (1 to 4 ml kg) 5 min prior to test.
• Body weight gain is the difference between the body weight of the animal at the time of dosing and the body weight of the animal following dosing.
• Food consumption is the difference in the weight of the food drawer between dosing and post testing.
• Water consumption is the difference in the weight of the water bottle between dosing and post testing.
• Fecal excretion is the difference in the weight of the empty fecal collection tube and the weight of the tube post testing.
• Urinary excretion is the difference in the weight of the empty urinary collection tube and the weight of the tube post testing.

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• Organic Chemistry (AREA)
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• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
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• 1998
  • 1998-07-02 US US09/109,558 patent/US6121260A/en not_active Expired - Fee Related
  • 1998-07-02 CN CN98807669A patent/CN1265033A/zh active Pending
  • 1998-07-02 EP EP98933135A patent/EP0996443A1/en not_active Withdrawn
  • 1998-07-02 KR KR1019997012624A patent/KR20010020610A/ko not_active Application Discontinuation
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• 2000
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